X-135985492-CG-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The ENST00000370695.8(SLC9A6):c.-5del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,074,422 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000023 (0 hom. 8 hem.)
• Consequence: SLC9A6 ENST00000370695.8 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 0.477

Genes affected

SLC9A6 (HGNC:11079): (solute carrier family 9 member A6) This gene encodes a sodium-hydrogen exchanger that is amember of the solute carrier family 9. The encoded protein localizes to early and recycling endosomes and may be involved in regulating endosomal pH and volume. Defects in this gene are associated with X-linked syndromic cognitive disability, Christianson type. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP6: Variant X-135985492-CG-C is Benign according to our data. Variant chrX-135985492-CG-C is described in ClinVar as [Benign]. Clinvar id is 422694.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC9A6	NM_001379110.1	c.-57+21del		intron_variant		ENST00000630721.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC9A6	ENST00000630721.3	c.-57+21del		intron_variant		4	NM_001379110.1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111033 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33371

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000809 AC: 3 AN: 37084 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000228 AC: 22 AN: 963389 Hom.: 0 Cov.: 27 AF XY: 0.0000268 AC XY: 8 AN XY: 298327

Gnomad4 AFR exome AF: 0.0000472

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111033 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33371

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000379

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 04, 2022

Variant summary: SLC9A6 c.-5delG is located in the untranslated mRNA region upstream of the initiation codon (in transcript NM_006359.3). This variant doesn't alter the consensus Kozak sequence, which plays a role in the recognition of the AUG (START) codon. In addition, this variant is located to intron 1 in other alternative transcripts (e.g. in NM_001177651.2 and NM_001379110.1), and results in a change that can be described as: c.-57+21delG, therefore could affect splicing: 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 37084 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.-5delG in individuals affected with Christianson Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2020

- -

Christianson syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Feb 23, 2024

The allele frequency of the c.-5del variant in SLC9A6 (NM_006359.2) is 0.02% in European (non-Finnish) sub population in gnomAD v2, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). Splice prediction analysis, using multiple computational tools does not suggest an impact to splicing (BP4). The c.-5del variant is observed in the hemizygous state in at least 2 unaffected individuals (internal database - GeneDx) (BS2). In sumarry, the c.-5del variant in SLC9A6 is classified as benign based on the ACMG/AMP criteria (BS1, BP4, BS2). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782431608; hg19: chrX-135067651;